P1154: STUDY ZILO-301: A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY OF ZILOVERTAMAB PLUS IBRUTINIB VS IBRUTINIB IN PATIENTS WITH RELAPSED OR REFRACTORY MANTLE CELL LYMPHOMA
Authors: S. Yazji, S. Hamburger, Y. Wang, S. Yavrom, A. Pietrofeso, R. Bliss, J. B. Breitmeyer, M. Dreyling, M. Wang
Journal: HemaSphere (2022)

Background: Zilovertamab (ZILO) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and has demonstrated additive/synergistic activity with anti-cancer agents including ibrutinib (Ibr). In the Phase 1/2 Study CIRM-0001, ZILO in combination with Ibr was well tolerated and demonstrated promising efficacy in heavily pretreated, relapsed and refractory (R/R) patients (pts) with mantle cell lymphoma (MCL). As of 1 Oct 2021, 26 evaluable pts were enrolled, the objective response rate (ORR) was 80.8 % of which 34.6% achieved complete response (CR), with a median progression free survival (mPFS) of 35.9 months (mos). The rationale for the novel enrichment design (Figure 1) of Study ZILO-301 is (1) there is an unmet medical need for pts with R/R MCL that only achieve a partial response (PR) or have stable disease (SD) on Ibr, (2) there is an early opportunity for marketing authorization based upon an accepted surrogate endpoint (namely ORR), and (3) a confirmatory study for regular approval is built into the study design based on PFS. The timeframe from initial accelerated marketing authorization to regular approval is shorter than historical approaches for this patient population. Additionally, in Study ZILO-302, the safety and efficacy of ZILO rescue therapy can be evaluated in pts that progress early on Ibr in Study ZILO-301. Aims: To evaluate the efficacy and safety of ZILO plus Ibr vs Ibr in R/R MCL pts. Methods: Study ZILO-301 is a Phase 3 randomized, double-blind, placebo-controlled, multicenter study under which pts with R/R MCL will initially receive single agent Ibr (560 mg daily). After 4 mos, pts who only have PR or SD will be randomized (1:1) to receive an infusion of ZILO or matching placebo (Pbo) and continue to receive Ibr. Study ZILO-301 key inclusion criteria: Aged ≥18 years, confirmed diagnosis of MCL, received ≥ 1 prior treatment for MCL (other than Bruton’s tyrosine kinase inhibitor), have measurable disease, and signed informed consent. Key exclusion criteria: History or current CNS involvement, significant cardiovascular disease, prior stem cell transplant requiring immunosuppressive therapy, or graft versus host disease. Efficacy assessments will be evaluated by a Blinded Independent Central Review Committee utilizing Lugano Classification (Cheson 2014). Results: Three analysis timepoints are planned. Analysis 1 is a futility assessment focused on ORR. Analysis 2 is an analysis for potential early marketing authorization (using accelerated assessment pathways by FDA and EMA), based upon ORR, duration of response (DOR), and safety. This analysis is expected to occur approximately 2 years after the first pt is enrolled in Study ZILO-301. Regardless of the Analysis 2 result, the study will proceed without modification. Analysis 3 is the end of study analysis for the primary endpoint of PFS and secondary endpoints of CR rate, duration of CR, time to CR on therapy, OS, proportion of pts experiencing Grade ≥ 3 neutrophil or platelet decrease, and overall safety. Regular marketing approvals would be sought based on Analysis 3. Figure 1 provides a schematic and subject flow for Study ZILO-301. Study ZILO-302 data may also support additional labeling for the combination of ZILO plus Ibr. Image:Summary/Conclusion: Study ZILO-301, a phase 3, multinational, double-blind, placebo-controlled study is open for enrollment in June 2022.